Antimicrobial compositions

ABSTRACT

A class of aminimides structurally characterizable as dipolar ions wherein a quaternary nitrogen atom is directly bonded to the nitrogen anion of an organic amide having a quaternary nitrogen atom in the acyl residue thereof exhibit broad spectrum inhibitory activity against bacterial and fungal organisms.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a class of nitrogenous compounds asantimicrobial agents for the control of bacterial and fungal growth.

2. Description of the Prior Art

Considerable effort has been directed during the past several decadestowards developing antimicrobial agents having a high activity against abroad spectrum of microorganisms including bacteria and fungi, but whichat the same time exhibit acceptable tolerable physiological properties.It is generally accepted that hexachlorophene of all of suchantimicrobials proposed to date comes about the closest to meeting thesedesiderata. Unfortunately the use of halogenated compounds of this typehas been severely restricted because of the recent unfortunate eventsstemming from what many feel amounted to a conspicuous misuse ofhexachlorophene. Accordingly a present need exists for an effectiveantimicrobial of this type devoid of the chemical characteristicsassociated with the indicated halogenated compounds.

It has recently been reported that certain fatty amines and fatty amidesevidence antimicrobial activity. Although the activity of thesecompounds fails to measure up to that demanded for a practicalantimicrobial agent, the low order of toxicity attributed to compoundsof this type renders these findings highly significant.

SUMMARY OF THE INVENTION

In accordance with the present invention a method is provided forinhibiting the growth of bacteria and fungi which comprises applying tosaid organisms or their loci an antimicrobially effective amount of acompound of the formula ##STR1## wherein n is an integer of from 10-16;X is chloro, bromo or iodo; and Y represents a radial selected from thegroup consisting of benzyldimethylammonium,2-(hydroxyethyl)dimethylammonium, N-methylpiperidinium,N-methylmorpholinium and pyridinium.

Further related compounds coming within the scope of this invention butwhose formuli do not conform to that given above include the following:##STR2## wherein X and n have the same meaning as given above.

The antimicrobial agents of this invention in essentially microconcentrations exhibit surprisingly effective broad spectrum inhibitoryactivity against bacterial and fungal organisms. Moreover, the dipolarion configuration of these compounds renders them highly hydrophilic innature which is an important property in respect of numerous useapplications for which the compounds are suited.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As indicated previously the practice of this invention resides in theuse of the antimicrobial agents described above as the active ingredientin a variety of conventional compositions for medicinal, cosmetic ordisinfectant purposes. These compositions can be in the form ofsolutions, as well as solid, liquid or pasty suspensions and emulsionswherein the carrier or vehicle portion is water, oil, or an organicsolvent, such as, for example, ethanol. Likewise these compositions canbe solid admixtures including the pulverulent form thereof.

Representative of the foregoing compositions include cosmetic oils,salves, cremes, pencils and powders; personal care items such as thespray, stick or powder deodorants, mouthwashes, hair rinses, skinlotions, foot powders and the like; and cleaning compositions such asdetergent bars, shampoos and toothpastes. Further, the antimicrobialagents of this invention can be advantageously employed in washing,rinsing, cleaning, disinfecting and preserving compositions fortextiles, leather, etc. Still a further important use of these agentscan be found in the cleaning and disinfecting compositions designed foruse in hospitals and such cleanliness sensitive industrialestablishments as dairies, breweries and laundries. The amount of theantimicrobial agent present in the contemplated compositions obviouslydepends on the particular use for which the overall composition isdesigned. Generally, in toothpaste, deodorants, cosmetics and footpowders and the like the amount of the antimicrobial agent ranges fromabout 0.1 to 3.0% based on the total weight of the composition. Inapplications of a cleansing and disinfecting nature as noted above, theconcentration of the agent in these instances can range up to about 10%.

The manner whereby the compounds useful in the practice of thisinvention can be prepared is well documented in the relevant art andthus need not be exemplified herein. All of the contemplated compounds,except one, can be prepared by a general procedure involving firstquaternizing an applicable tertiary amine with an ester of halo aceticacid, preferably chloro methyl or ethyl acetate, to provide thecorresponding quaternary ammonium derivative which is then converted tothe desired aminimide by reaction with unsymmetrical dimethyl hydrazineand an appropriate long chain terminal epoxide, all as described indetail in U.S. Pat. No. 3,485,806. The applicable tertiary amines forpreparing the contemplated compounds as aforesaid include triethylamine,benzyldimethylamine, 2-(hydroxyethyl)dimethylamine, N-methylpiperidine,N-methylmorpholine, pyridine, and N,N-dimethylglycinate, the latterproviding a bisaminimide in accordance with U.S. Pat. No. 3,485,806 whenemploying equivalent proportions of the dimethyl hydrazine and epoxide.The remaining contemplated compound can be obtained by quaternizing anester isonicotinic acid with benzylchloride followed by conversion ofthe ester group of the quaternized product to the aminimide residue viathe procedure of the aforesaid patent.

EXAMPLE

For the purpose of illustrating the antimicrobic activity of theaminimides of the present invention, two gram negative bacteria, fivegram positive bacteria and two representative fungi were used in aconventional test procedure for determining inhibitory effect. Theidentification of these test organisms and their source follows:

    ______________________________________                                        Organism        Source                                                        ______________________________________                                        Escherichia coli                                                                              Clinical Isolate                                              Psendomonas aeruginosa                                                                        ATCC #10145                                                   Streptococcus faecalis                                                                        Clinical Isolate                                              (grp. D)                                                                      Streptococcus pyogenes                                                                        Clinical Isolate                                              Staphylococcus aureus                                                                         Hospital Infection                                            Corynebacterium ATCC #10700                                                   Nocardia asteroides                                                                           ATCC #3308                                                    Saccaharomyces cerevisiae                                                                     Fleishman                                                     Candida albicans                                                                              Michigan State University                                                     Plant Pathology Fungi Collection                              ______________________________________                                    

In the test procedure observed, representative aminimides were dissolvedin water or 95% ethanol to provide standard solutions having aconcentration of 1.0 mg of the test compound per ml of the solvent. Afurther test series was prepared by diluting with sterile Trypticase SoyBroth to concentrations of 100 ug/ml. Compounds more active than at 100ug/ml were further diluted in a subsequent test or tests.

Following the preparations of the test solutions as noted above, onedrop (0.4±0.01 ml.) of an 18-hour broth culture containing 10⁹ to 10¹²organisms per ml. was added to about 10 cc of each starting dilution ofthe indicated test compounds as well as to a like sample of plain brothserving as a positive control. After innoculation, the test samples arethoroughly mixed and then incubated at 35° C. in a 5% carbon dioxideatmosphere.

After an 18 hour period of incubation, the minimal inhibitoryconcentration (MIC) of each compound was determined for each testmicroorganism. The MIC value is defined as the lowest concentration(ug/ml) of the test compound at which no microscopic evidence of growthis observed. In those instances where the MIC exceeded 1000 ug/ml thecompound was rated non-inhibitory (NI). Under those circumstances wherethe test compond itself causes turbidity so that the MIC proveddifficult to determine in accordance with the above procedure, a sample(0.015 ml.) of the well-agitated broth or broths in question wereinnoculated into a Trypticase Soy agar containing 5% defibrinated sheepblood. The test plate wold then be incubated at 35° C. for 18 hours andthereupon examined for growth.

The identification of the representative compounds tested in accordancewith the foregoing procedure is set forth as follows:

    __________________________________________________________________________     ##STR3##                                                                     COMPOUND Y                 n                                                  __________________________________________________________________________    A        benzyldimethylammonium                                                                          14                                                 B        "                 10                                                 C        2-(hydroxyethyl)dimethylammonium                                                                14                                                 D        N-methylpiperidinium                                                                            14                                                 E        N-methylmorpholinium                                                                            14                                                 F        pyridinium        14                                                           ##STR4##                                                            I                                                                                       ##STR5##                                                            __________________________________________________________________________

The results of tests are given in the following Table I.

                                      TABLE I                                     __________________________________________________________________________    MICs (μg/ml)                                                               compound--     *  A  B  C D  E  F  H  I                                       __________________________________________________________________________    organism                                                                      Escherichia coli                                                                             NI 100                                                                              NI NI                                                                              1000                                                                             100                                                                              100                                                                              NI NI                                      Pseudomonas aeruginosa                                                                       1000                                                                             NI 1000                                                                             NI                                                                              NI NI NI NI NI                                      Streptococcus faecalis (grp. D)                                                              10 10 100                                                                              10                                                                              10 10 10 100                                                                              10                                      Streptococcus pyrogenes                                                                      1  1  10 1 1  1  1  1  10                                      Staphylococcus aureus                                                                        1  1  100                                                                              10                                                                              10 10 10 1000                                                                             1                                       Corynebacterium sp.                                                                          1  1  10 10                                                                              1  10 1  10 10                                      Nocardia asteroides                                                                          10 10 100                                                                              10                                                                              10 10 10 100                                                                              10                                      Candida albicans                                                                             NI NI 100                                                                              NI                                                                              10 100                                                                              10 10 100                                     Saccharomyces cerevisiae                                                                     10 10 100                                                                              10                                                                              10 10 10 100                                                                              10                                      __________________________________________________________________________     *HEXACHLOROPHENE                                                         

What is claimed is:
 1. A method of inhibiting the growth of bacteria andfungi which comprises applying to said organisms or their loci anantimicrobially effective amount of a compound of the formula ##STR6##wherein Y represents a quaternary nitrogen residue selected from thegroup consisting of ##STR7## wherein n is an integer of from 10-16; andX is chloro, bromo or iodo.
 2. The method of claim 1 wherein X of saidformula is chloro.
 3. The method of claim 2 wherein n of said formula is10.
 4. The method of claim 2 wherein n of said formula is
 12. 5. Themethod of claim 2 wherein n of said formula is
 14. 6. The method ofclaim 2 wherein n of said formula is 16.